NOD-like receptors in intestinal homeostasis and epithelial tissue repair

Abstract

The intestinal epithelium constitutes a dynamic physical barrier segregating the luminal content from the underlying mucosal tissue. Following injury, the epithelial integrity is restored by rapid migration of intestinal epithelial cells (IECs) across the denuded area in a process known as wound healing. Hence, through a sequence of events involving restitution, proliferation and differentiation of IECs the gap is resealed and homeostasis reestablished. Relapsing damage followed by healing of the inflamed mucosa is a hallmark of several intestinal disorders including inflammatory bowel diseases (IBD). While several regulatory peptides, growth factors and cytokines stimulate restitution of the epithelial layer after injury, recent evidence in the field underscores the contribution of innate immunity in controlling this process. In particular, nucleotide-binding and oligomerization domain-like receptors (NLRs) play critical roles in sensing the commensal microbiota, maintaining homeostasis, and regulating intestinal inflammation. Here, we review the process of intestinal epithelial tissue repair and we specifically focus on the impact of NLR-mediated signaling mechanisms involved in governing epithelial wound healing during disease.

Figure 1

Signal transduction pathways involved in intestinal epithelial tissue repair. TLR2 engagement induces TFF3 release from mucin (MUC2) secreting Goblet cells. Released TFF3 is detected by adjacent enterocytes via EGFR (ErbB) transactivation leading to PI3K and MAPK (ERK, p38) signaling. Similarly, TLR4 activation at the basal side of the IECs permits COX1/2-derived PGE2 secretion essential for efficient cell proliferation. Both EGF and TGF-α induce epithelial restitution and proliferation by stimulating ErbB receptors and activating downstream p38, ERK and NF-κB signaling cascades. On the other hand, TGF-β via its type I and II serine/threonine receptors induces the translocation of SMAD2/3/4 complex to the nucleus and regulates a gene transcription program fundamental for epithelial cell differentiation and restitution.

Figure 2

Simplified NLR pathways engaged in intestinal homeostasis. Upon microbial sensing, NOD1 and NOD2 recruit the adaptor protein RIP2 via CARD-CARD interactions. Activated RIP2 binds to the E3 ubiquitin ligases TRAFs and IAPs triggering NF-κB and MAPK signaling. Similarly, the adaptor protein ASC bridges the activated inflammasome NLRs (NLRP3, 6 and 12) to pro-caspase-1 through both PYD and CARD domains, respectively. Formation of the inflammasome complex triggers auto-proteolytic cleavage and activation of caspase-1 subsequently leading to maturation and release of IL-1β and IL-18. Activation of both NOD signaling and inflammasome pathways contributes to the maintenance of intestinal homeostasis against resident commensal microbes.